Aberrant distribution and function of plasmacytoid dendritic cells in patients with ankylosing spondylitis are associated with unfolded protein response

The unfolded protein response (UPR) is a highly conserved pathway that allows cells to respond to stress in the endoplasmic reticulum caused by an accumulation of misfolded and unfolded protein. This is of great importance to secretory cells because, in order for proteins to traffic from the endoplasmic reticulum (ER), they need to be folded appropriately. While a wealth of literature has implicated UPR in immune responses, less attention has been given to the role of UPR in T cell development and function. This review discusses the importance of UPR in T cell development, homeostasis, activation, and effector functions. We also speculate about how UPR may be manipulated in T cells to ameliorate pathologies.

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Balancing life with glycoconjugates: Monitoring unfolded protein response-mediated anti-angiogenic action of tunicamycin by Raman spectroscopy

Pure and Applied Chemistry ◽

10.1351/pac-con-12-01-06 ◽

2012 ◽

Vol 84 (9) ◽

pp. 1907-1918 ◽

Cited By ~ 2

Author(s):

Maria O. Longas ◽

Ashok Kotapati ◽

Kilari PVRK Prasad ◽

Aditi Banerjee ◽

Jesus Santiago ◽

...

Keyword(s):

Raman Spectroscopy ◽

Er Stress ◽

Unfolded Protein Response ◽

Competitive Inhibitor ◽

Protein Glycosylation ◽

Endothelial Cell Proliferation ◽

Dependent Manner ◽

Unfolded Protein ◽

And Function ◽

Protein Response

Asparagine-linked protein glycosylation is a hallmark for glycoprotein structure and function. Its impairment by tunicamycin [a competitive inhibitor of N-acetylglucos-aminyl 1-phosphate transferase (GPT)] has been known to inhibit neo-vascularization (i.e., angiogenesis) in humanized breast tumor due to an induction of endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR). The studies presented here demonstrate that (i) tunicamycin inhibits capillary endothelial cell proliferation in a dose-dependent manner; (ii) treated cells are incapable of forming colonies upon its withdrawal; and (iii) tunicamycin treatment causes nuclear fragmentation. Tunicamycin-induced ER stress-mediated UPR event in these cells was studied with the aid of Raman spectroscopy, in particular, the interpretation of bands at 1672, 1684, and 1694 cm–1, which are characteristics of proteins and originate from C=O stretching vibrations of mono-substituted amides. In tunicamycin-treated cells, these bands decreased in area as follows: at 1672 cm–1 by 41.85 % at 3 h and 55.39 % at 12 h; at 1684 cm–1 by 20.63 % at 3 h and 40.08 % at 12 h; and also at 1994 cm–1 by 33.33 % at 3 h and 32.92 % at 12 h, respectively. Thus, in the presence of tunicamycin, newly synthesized protein chains fail to arrange properly into their final secondary and/or tertiary structures, and the random coils they form had undergone further degradation.

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Transient activation of the UPRER is an essential step in the acquisition of pluripotency during reprogramming

10.1101/472787 ◽

2018 ◽

Author(s):

Milos S. Simic ◽

Erica Moehle ◽

Robert T. Schinzel ◽

Franziska Lorbeer ◽

Damien Jullié ◽

...

Keyword(s):

Unfolded Protein Response ◽

Cellular Reprogramming ◽

Pluripotent State ◽

Form And Function ◽

Unfolded Protein ◽

Er Stress Response ◽

Transient Activation ◽

Low Efficiency ◽

And Function ◽

Protein Response

AbstractSomatic cells can be reprogrammed into pluripotent stem cells by the forced expression of the OCT4, SOX2, KLF4 and c-MYC transcription factors. This process requires the reshaping of not only epigenetic landscapes, but the global remodeling of cell identity, structure, and function including such basic processes of metabolism and organelle form and function. Cellular reprogramming is a stochastic process with only a marginally measureable fraction of cells successfully crossing these, and many other, cellular epitomes to acquire the fully pluripotent state. We hypothesize that this variation is due, in part, by variable regulation of the proteostasis network and its influence upon the protein folding environment within cells and their organelles upon the remodeling process. We find that the endoplasmic reticulum unfolded protein response (UPRER), the heat-shock response (HSR) and the mitochondrial unfolded protein response (UPRmt), which monitor and ensure the quality of the proteome of, respectively, the ER, the cytosol and the mitochondria during stress, are activated during cellular reprogramming. Particularly, we find that the UPRER is essential for reprograming, and ectopic, transient activation of the UPRER, either genetically or pharmacologically, enhances the success of cells to reach a pluripotent state. Finally, and most revealing, we find that stochastic activation of the UPRER can predict the reprogramming efficiency of naïve cells. The results of these experiments indicate that the low efficiency and stochasticity of cellular reprogramming is partly the result of the inability to initiate a proper ER stress response for remodeling of the ER and its proteome during the reprogramming process. The results reported here display only one aspect of the proteostasis network and suggest that proper regulation of many more components of this network might be essential to acquire the pluripotent state.

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Role of unfolded protein response in genital malformation/damage of male mice induced by flutamide

Human & Experimental Toxicology ◽

10.1177/0960327120937049 ◽

2020 ◽

Vol 39 (12) ◽

pp. 1690-1699

Author(s):

H Yu ◽

K Wen ◽

X Zhou ◽

Y Zhang ◽

Z Yan ◽

...

Keyword(s):

Unfolded Protein Response ◽

Messenger Rna ◽

Hypoxia Inducible Factor ◽

Reproductive Organs ◽

Pregnant Mouse ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

And Function ◽

Protein Response

The unfolded protein response (UPR) is one of a switch of autophagy and apoptosis, and the endoplasmic reticulum stress (ERS) which inducing UPR plays a role in the malformations caused by some genetic and environmental factors. Exposure to flutamide during pregnancy will also cause abnormalities in some male offspring reproductive organs such as cryptorchidism. In this study, after administered the pregnant mouse orally at a dose of 300 mg/kg body weight every day during gestational day (GD)12 to GD18, flutamide can not only caused hypospadias in the male mouse offspring but also damaged the morphology and function of their testis. And the expression of UPR-related genes and proteins, autophagy, apoptosis, and angiogenesis-related genes of the damaged/teratogenic testis and penis in the mice were investigated to determine the role of UPR in this model. It was found that flutamide activated maybe the Atg7-Atg3-Lc3 pathway through the UPR pathway, caused cells excessive autophagy and apoptosis, and inhibited the formation of penile and testicular blood vessels by activating UPR and affecting the messenger RNA level of vascular endothelial growth factor and hypoxia-inducible factor 1.

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Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts

AJP Cell Physiology ◽

10.1152/ajpcell.00017.2014 ◽

2014 ◽

Vol 306 (12) ◽

pp. C1176-C1183 ◽

Cited By ~ 53

Author(s):

Sobia Iqbal ◽

David A. Hood

Keyword(s):

Oxidative Stress ◽

Unfolded Protein Response ◽

Mitochondrial Morphology ◽

Related Protein ◽

Mitochondrial Fragmentation ◽

Signaling Mechanism ◽

Unfolded Protein ◽

Mitochondrial Motility ◽

And Function ◽

Protein Response

Mitochondria are dynamic organelles, capable of altering their morphology and function. However, the mechanisms governing these changes have not been fully elucidated, particularly in muscle cells. We demonstrated that oxidative stress with H2O2 resulted in a 41% increase in fragmentation of the mitochondrial reticulum in myoblasts within 3 h of exposure, an effect that was preceded by a reduction in membrane potential. Using live cell imaging, we monitored mitochondrial motility and found that oxidative stress resulted in a 30% reduction in the average velocity of mitochondria. This was accompanied by parallel reductions in both organelle fission and fusion. The attenuation in mitochondrial movement was abolished by the addition of N-acetylcysteine. To investigate whether H2O2-induced fragmentation was mediated by dynamin-related protein 1, we incubated cells with mDivi1, an inhibitor of dynamin-related protein 1 translocation to mitochondria. mDivi1 attenuated oxidative stress-induced mitochondrial fragmentation by 27%. Moreover, we demonstrated that exposure to H2O2 upregulated endoplasmic reticulum-unfolded protein response markers before the initiation of mitophagy signaling and the mitochondrial-unfolded protein response. These findings indicate that oxidative stress is a vital signaling mechanism in the regulation of mitochondrial morphology and motility.

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